Intravenous Versus Oral Iron for Treatment of Iron Deficiency in Non-hemodialysis-dependent Patients With Chronic Kidney Disease

Anne Marie Liles

Disclosures

Am J Health Syst Pharm. 2012;69(14):1206-1211. 

In This Article

Oral Versus I.V. Iron in Patients Receiving ESAs

Stoves et al

The first prospective, randomized controlled trial comparing i.v. and oral iron in ND-CKD patients was conducted by Stoves et al.[11] in 2001. Forty-five anemic patients (hemoglobin concentration of <11.0 g/dL) were treated for an average of 5.2 months with either 200 mg oral ferrous sulfate three times daily (n = 23) or 300 mg i.v. iron sucrose once monthly (n = 22). Erythropoietin was also initiated at a dosage of 2000 units two times a week and then adjusted based on hemoglobin response. Baseline data were similar between groups for mean hemoglobin, ferritin, and hypochromia.

Mean ESA dosage requirements did not significantly differ between the i.v. and oral iron groups (41.6 and 33.5 units/kg/week, respectively), nor did mean final hemoglobin concentrations (12.5 and 12.2 g/dL, respectively). While mean ferritin concentrations were significantly higher in the i.v. group (330 ng/mL versus 95 ng/mL), there was no significant difference in the frequency of red cell hypochromia, which Stoves et al. suggested is a more direct measure of iron supply for erythropoiesis.

Five patients (55%) in the oral iron group had diabetes, compared with none in the i.v. group, which may have confounded the results as diabetes is associated with greater inflammation and the potential for decreased iron absorption.[12] In addition, the number of patients being treated with angiotensin-converting-enzyme inhibitors and angiotensin-receptor antagonists was higher in the oral iron group, potentially confounding the results due to potential drug interaction with ESAs. This drug interaction is proposed to be a result of the association of the renin-angiotensin system with endogenous erythropoietin production and results in the subsequent blunting of response to the ESA.[13–15] The rate of adverse gastrointestinal effects was higher in the oral iron group; however, no details regarding specifics of these adverse effects were given, only that they were of mild severity. Statistical test results were not specifically reported in this study, only statements as to whether a difference was statistically significant. The investigators concluded that monthly 300-mg doses of i.v. iron sucrose were not superior to 200-mg doses of oral ferrous sulfate administered three times daily with regard to hemoglobin response and ESA dosage requirements.

Aggarwal et al

A subsequent study comparing i.v. and oral iron in ND-CKD patients was published by Aggarwal et al.[16] in 2003. Forty patients were randomized to receive either oral ferrous sulfate 200 mg three times daily (n = 20) or i.v. iron dextran 200 mg two times a month (n = 20) for a duration of three months. In addition, erythropoietin was initiated in all patients at a dosage of 2000 units two times a week. Unlike the study by Stoves et al.,[11] this dosage was not adjusted during the study. Baseline hemoglobin values were well below the KDOQI goal of 11–12 g/dL[1] (6.26 ± 1.0 g/dL for the oral ferrous sulfate group and 5.83 ± 0.6 g/dL for the i.v. iron dextran group). Baseline ferritin concentrations (190.27 ± 33.23 ng/mL in patients receiving oral iron and 181.44 ± 45.33 ng/mL in the group receiving i.v. iron) and TSAT (63.56% ± 11.10% and 59.78% ± 10.36%, respectively) levels were above the KDOQI's recommended goals for ferritin (>100 ng/mL) and TSAT (>20%).[1] After three months of treatment, hemoglobin levels in both groups increased from baseline; however, the i.v. iron group had a significantly higher mean hemoglobin concentration at three months compared with the oral iron group (10.05 ± 0.9 g/dL versus 8.94 ± 1.17 g/dL, p < 0.001). The i.v. iron group also had significant increases in TSAT and ferritin levels (p < 0.01 and p < 0.001, respectively), while the oral iron group had significant decreases in these values (p < 0.001 for both values). The authors hypothesized that the use of oral iron could eventually result in a negative iron balance and a subsequent decrease in hemoglobin levels, concluding that i.v. iron was a better choice than oral iron in ND-CKD patients treated with an ESA. No patients in either group developed noteworthy adverse effects; the number of patients experiencing gastrointestinal complications was not given. The external validity of this study is limited by the participants' uncharacteristically low baseline hemoglobin values. In addition, because patients were iron replete at baseline, it is likely that the increases in hemoglobin resulted from the administration of the ESA rather than iron.

Charytan et al

A similar Phase II/III open-label trial conducted by Charytan et al.[17] randomized 96 ND-CKD patients to receive either oral ferrous sulfate 325 mg three times daily (n = 48) or i.v. iron sucrose 200 mg every 7 days for a total of five doses (n = 48). Like the 2003 Aggarwal et al. study, erythropoietin 2000 units weekly was initiated, with no changes in the dosage during the study. Patients with hemoglobin concentrations of <10.5 g/dL, TSAT levels of <25%, and ferritin concentrations of <300 ng/mL were included in the study. The treatment duration was 29 days with final outcomes measured on day 43, two weeks after the last dose of either oral or i.v. iron. Both i.v. and oral iron groups had a significant mean increase in hemoglobin from baseline to day 43 (0.7 g/dL [p < 0.0001] and 1.0 g/dL [p < 0.0001], respectively); however, the difference between the groups was not significant. There was a significant difference in the change from baseline in ferritin levels between groups (a mean decrease of 5.1 ng/mL in the oral iron group versus a mean increase of 288.0 ng/mL for the i.v. iron group, p < 0.0001). In addition, the i.v. iron group had a mean increase of 4.5% in TSAT levels from baseline (p < 0.0001), while the oral iron group had an increase of only 0.5% (p = 0.567). The frequency of gastrointestinal symptoms was greater in the oral iron group than the i.v. group (constipation, 35.4% versus 12.5%; nausea, 10.4% versus 4.2%; vomiting, 8.3% versus 0%; and diarrhea, 8.4% versus 0%). Taste disturbances were more common in the i.v. iron group. No patients experienced serious adverse effects, including anaphylactic-type reactions. The investigators concluded that both i.v. and oral iron resulted in similar hemoglobin responses but that the lack of significant change in iron stores (TSAT levels) with oral iron may lead to an eventual loss of response to ESA therapy.

Van Wyck et al

A Phase III trial conducted by Van Wyck et al.[18] attempted to control for ESAs as a confounder by limiting study inclusion to ND-CKD patients who were receiving a stable dosage of an ESA for at least eight weeks or who had not been treated with an ESA. Patients' ESA dosages were maintained throughout the duration of the trial. A total of 188 patients were randomized to receive either 325 mg oral ferrous sulfate three times daily for 56 days (n = 93) or 1000 mg i.v. iron sucrose in divided doses over 14 days (n = 95). Other inclusion criteria included a hemoglobin concentration of ≤11.0 g/dL, a TSAT level of ≤25%, and a ferritin concentration of ≤300 ng/mL. A greater percentage of patients in the i.v. iron group achieved an increase of ≥1.0 g/dL in hemoglobin concentration compared with the oral iron group (44.3% [n = 35] versus 28.0% [n = 23], p = 0.0344). Ferritin and TSAT values increased significantly from baseline in both groups, but the increase in ferritin in the i.v. iron group was significantly greater than that in the oral group. More patients in the i.v. iron group reported nonserious adverse effects than in the oral iron group (22% [n = 20] versus 19% [n = 17], respectively). Taste disturbances were the most common gastrointestinal complaint with i.v. iron, and constipation, diarrhea, nausea, vomiting, and dyspepsia were the most common adverse effects reported in patients treated with oral iron. Three patients were reported to have experienced symptomatic hypotension with i.v. iron. The investigators concluded that 1000 mg i.v. iron sucrose administered in divided doses was superior to 325 mg oral ferrous sulfate given three times daily in ND-CKD patients with anemia and iron deficiency.

Spinowitz et al

A Phase III trial by Spinowitz et al.[19] randomized 304 ND-CKD patients to receive 200 mg oral ferrous fumarate daily for 21 days (n = 76) or two 510-mg doses of i.v. ferumoxytol within 2–8 days (n = 228). Similar to the study conducted by Van Wyck et al., patients were included only if they were receiving a stable ESA dosage or not taking an ESA. ESA dosages were not changed and new regimens of ESAs were not initiated during the study. Both groups had a mean hemoglobin concentration of 9.96 g/dL, a mean ferritin concentration of >100 ng/mL at baseline, and a mean TSAT level of <20%. Final outcomes were measured on day 35, two weeks after the last dose of oral iron was administered. The mean increase in hemoglobin concentration from baseline was greater in the i.v. group (0.82 ± 1.24 g/dL versus 0.16 ± 1.02 g/dL, p < 0.0001). Increases in ferritin concentrations and TSAT levels were also greater in the i.v. group (mean ferritin increase, 381.7 ng/mL versus 6.9 ng/mL, p < 0.0001; mean TSAT increase, 9.8% versus 1.3%, p < 0.0001). Treatment-related adverse effects occurred more frequently in the oral iron group (24.0% [n = 18] versus 10.6% [n = 23]). Constipation and vomiting were most frequently reported with oral iron. The investigators concluded that i.v. ferumoxytol was more effective than oral ferrous fumerate in increasing hemoglobin values in ND-CKD patients.

Qunibi et al

The most recent trial comparing i.v. and oral iron in ND-CKD patients was conducted by Qunibi et al.[20] This Phase III trial included patients with hemoglobin concentrations of ≤11.0 g/dL, TSAT levels of ≤25%, and ferritin concentrations of ≤300 ng/mL. A total of 255 patients were randomized to receive oral ferrous sulfate 325 mg three times daily for 56 days (n = 103) or 500–1000 mg of i.v. ferric carboxymaltose (n = 152). The initial dose of i.v. ferric carboxymaltose was 1000 mg, and 500-mg doses were subsequently administered on day 17 and again on day 31 if a patient's TSAT level remained at <30% and the ferritin concentration was <300 ng/mL, for a maximum of two additional doses. Forty-two percent of patients received more than one dose of i.v. ferric carboxymaltose. Mean increases in ferritin and TSAT values from baseline to day 56 were greater in the i.v. iron group (ferritin, 358.8 ± 178.4 ng/mL versus 25.8 ± 49.4 ng/mL, p < 0.001; TSAT, 12.1% ± 8.8% versus 7.0% ± 10.3%, p < 0.001). However, ferritin concentrations in the i.v. group did show significantly greater mean increases than the oral group on day 14 after the administration of only 1000 mg of i.v. iron (p < 0.001). Hemoglobin changes were also significantly greater in the i.v. group (1.05 ± 1.10 g/dL versus 0.70 ± 1.25 g/dL, p = 0.034).

It should also be noted that the levels of iron stores used to determine the need for additional i.v. iron doses were greater than the recommended goals. In clinical practice, it is uncommon for patients to receive >1 g of i.v. iron in a 30-day period, while oral iron is typically dosed at a maximum of 200 mg elemental iron daily (ferrous sulfate 325 mg three times daily contains 195 mg of elemental iron). Constipation was the only adverse effect whose frequency significantly differed between groups (17.5% with oral iron versus 1.4% with i.v. iron, p < 0.001). The authors concluded that i.v. ferric carboxymaltose was more effective and better tolerated than oral ferrous sulfate for the treatment of iron deficiency in ND-CKD patients. However, given the disparity in dosing, the 0.35-g/dL difference in mean hemoglobin concentrations may not be clinically significant.

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